During early stages of pulmonary vascular development, angiogenesis, vasculogenesis and lymphangiogenesis play major roles in the establishment of the functional vascular and lymphatic networks. VEGF-D expression is strongly expressed in developing lung mesenchyme (2) and functions by binding the endothelial cell tyrosine kinase VEGFR-3. VEGF-D has been shown to induce lymphangiogenesis and the tumor metastasis in in vitro and in transgenic models. Signaling through VEGFR-3 has been demonstrated to induce lymphangiogenesis and maintenance of lymphatic vessels in vitro and in adult transgenic animals (4,6). However, there is no information on the role of VEGF-D in lung lymphangiogenesis. Pulmonary lymphatics are critical at birth for fluid clearance and normal lung function. Based on the known function of VEGFR-3 signaling and the unique pattern of expression of VEGF-D, we hypothesize that: VEGF-D is required for pulmonary lymphatic development and endothelial cell differentiation from a vascular to lymphatic lineage.